Cardiovascular disease encompasses a number of disorders that affect the muscle and/or blood vessels of the heart, peripheral blood vessels, muscles and various organs. It is established in the art that inflammatory and immunoregulatory processes are implicated in the pathogenesis of various forms of cardiovascular disease.
For example, inflammatory immune responses have been shown to contribute to the pathogenesis of atherosclerosis. Elevated levels of C-reactive protein (CRP) have been associated with up to an 8.6 fold increase in the relative risk of symptomatic atherosclerosis (Biasucci, L., et al., Circulation 1999, 99:855-860). Elevated levels of CRP also predict patients that are at elevated risk of myocardial infarction (MI) or stroke, and it has also been associated with poor prognosis in unstable angina (Vorchheimer, D., et al., JAMA 2001, 286:2154-2156). Binding C1q CRP activates the classical complement pathway and may lead to direct myocardial damage, coronary smooth muscle or endothelial cell death and subsequent atherosclerotic plaque rupture (Agrawal, A., et al., J Immunol 2001, 166:3998-4004). Furthermore, a recent study demonstrated that elevated levels of CRP are able to identify patients that die of sudden cardiac death 9 years prior to the event (Albert, C., et al., Circulation 2002, 105:2595-9). These studies also imply that long-term inflammatory exposure and elevated CRP levels may contribute to the progression of acute coronary syndromes (Buffon, A., et al., NEJM 2002, 347:55-7). Activation of inflammatory cells resident within an atherosclerotic plaque may elaborate enzymes capable of degrading extracellular matrix and lead to plaque rupture. Alternatively, these inflammatory cells may directly kill endothelial and smooth muscle cells. A number of studies have demonstrated that patients with unstable angina have peripheral T-cells that make enhanced levels of interferon gamma compared to patients with stable angina. Furthermore, there appears to be clonal expansion of a CD4+CD28null T-cell population in these patients, which appear to be cytotoxic and can kill endothelial cells, an effect enhanced by CRP (Nakajima, T., et al., Circulation 2002, 105:570-5).
Cytokines are critical regulators of the T-helper 1 (Th1) and Th2 T-cell responses. The Th1 response results in pro-inflammatory cytokine release characterized by macrophage activation and, if unopposed, may result in tissue damage. The Th2 response results in a humoral immune response, B-cell activation and an allergic reaction (Neurath, M., et al., Nat Med 2002, 8:567-73). A number of Th1 type cytokines including TNF, IL-6 and the chemokine MCP-1 are elevated in unstable angina (AJC 2001, 88(8A):10K-15K). Recently, IL-18 has been found to be an independent marker for an adverse outcome in patients diagnosed with acute coronary syndrome (Blankenberg, S., et al., Circulation 2002, 106:24-30). Elevated levels of IL-18 have also been found to correlate with ulcerated, symptomatic carotid artery lesions (Mallat, Z., et al., Circulation 2001, 104:1598-603). In a mouse model of atherosclerotic plaque development in ApoE deficient mice, IL-18 was shown to accelerate and enhance plaque formation, and IL-18 binding protein enhanced smooth muscle proliferation, which would promote plaque stability by increasing the thickness of the cap, and reduced the number of infiltrating macrophages and T-cells (Mallat, Z., et al., Circ Res. 2001, 89:E41-5). Studies such as these establish a sound basis for implicating inflammatory and immunoregulatory responses in cardiovascular disease.
There is an unmet need in the art for treating cardiovascular disease by targeting the immunopathology of the disease. Embodiments of the present invention address such needs by providing compositions and methods for treating cardiovascular disease by modulating the inflammatory and immunoregulatory responses associated with cardiovascular disease.